The stimulation of protein degradation in muscle by Ca2+ is mediated by prostaglandin E2 and does not require the calcium-activated protease.
Treatment of isolated rat skeletal muscles with the Ca2+ ionophores, A23187 or ionomycin, increased overall protein degradation 45-140%. Removal of extracellular Ca2+ reduced overall proteolysis and most of the stimulation by A23187. Treatment of the muscles with the sulfhydryl inhibitor, mersalyl, completely inactivated the Ca2+-activated protease without altering overall protein breakdown or the stimulation by A23187. This agent did not inhibit the lysosomal protease, cathepsin B, in the muscle; however, leupeptin and Ep-475, which inhibit this enzyme in intact cells, decreased the stimulation of proteolysis by Ca2+. Thus, this effect does not require the Ca2+-activated enzyme, but seems to involve lysosomal proteases. Prostaglandin E2 (PGE2) and its precursor arachidonic acid, were previously shown to stimulate protein degradation in rat muscle through an effect on lysosomal function. We tested whether the enhancement of muscle proteolysis by Ca2+ ionophores may result from increased synthesis of PGE2. A23187 increased release of PGE2 and PGF2 alpha by the muscles 3-4-fold. High extracellular potassium also markedly promotes muscle proteolysis, apparently by increasing intracellular Ca2+, and this treatment also stimulates prostaglandin production. Indomethacin and aspirin, which inhibit the cyclooxygenase, and mepacrine, which inhibits the Ca2+-activated phospholipase A2, markedly reduced the increase in prostaglandin production. These agents also reduced the enhancement of protein degradation by Ca2+ or high K+. Thus, Ca2+ appears to promote protein breakdown by stimulating synthesis of PGE2, which in turn activates the lysosomal apparatus.
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D015237:Dinoprost; D015232:Dinoprostone; D010450:Endopeptidases / Q000378:metabolism*; D004987:Ethers / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D015759:Ionomycin; D009124:Muscle Proteins / Q000378:metabolism*; D009132:Muscles / Q000187:drug effects; D011188:Potassium / Q000494:pharmacology; D011458:Prostaglandins E / Q000096:biosynthesis / Q000494:pharmacology*; D011460:Prostaglandins F / Q000096:biosynthesis; D051381:Rats
D004987:Ethers; D009124:Muscle Proteins; D011458:Prostaglandins E; D011460:Prostaglandins F; D000001:Calcimycin; D015759:Ionomycin; D015237:Dinoprost; D010450:Endopeptidases; D015232:Dinoprostone; D001241:Aspirin; D011188:Potassium; D002118:Calcium; D007213:Indomethacin